Methods for determining differences in alpha-4 integrin activity by correlating differences in sVCAM and/or sMAdCAM levels

Abstract

Provided herein is a method of monitoring the change of the alpha-4 integrin activities in an individual by correlating with the soluble vascular cell adhesion molecule (sVCAM) and/or soluble mucosal addressin cell adhesion molecule (sMAdCAM) levels. Particularly, this method can be used, for example, to evaluate the pharmacokinetics and pharmacodynamics (PK/PD) of an alpha-4 integrin inhibitor used to treat a disease associated with pathological or chronic inflammation.

What is claimed is: 
     
       1. A method of treating multiple sclerosis in an individual, comprising:
 a) measuring a soluble molecule in a first biological sample obtained from the individual immediately before administration of a first dose of natalizumab, wherein the soluble molecule is sVCAM and/or sMAdCAM; 
 b) administering the first dose of natalizumab to the individual; 
 c) measuring the sVCAM and/or sMAdCAM in a second biological sample, wherein the second biological sample has been obtained from the individual within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after administration of the first dose of natalizumab; 
 d) determining whether there is a decrease in the levels of the sVCAM and/or sMAdCAM between the first and second biological samples, wherein the decrease correlates with a decrease in alpha-4 integrin activity in the individual, and thereby determining whether there is a difference in alpha-4 integrin activity in the individual after administration of the first dose of natalizumab compared with before administration of the first dose of natalizumab; and 
 e) administering a second dose of natalizumab to the individual, wherein the second dose of the natalizumab is based on whether there is a decrease in the levels of the sVCAM and/or sMAdCAM between the first and second biological samples, 
 
       wherein: 
       the method comprises detecting no decrease or a statistically insignificant decrease (p>0.05) in the levels of sVCAM and/or sMAdCAM between the first and second biological samples, thereby determining that the first dose of the natalizumab is ineffective and the method further comprises adjusting the second dose of the natalizumab wherein the second dose is higher than the first dose. 
     
     
       2. The method of  claim 1 , wherein alpha-4 integrin activity is alpha-4 beta-1 integrin activity, and wherein the soluble molecule is sVCAM. 
     
     
       3. The method of  claim 1 , wherein the first and/or the second biological sample is selected from the group consisting of a tissue, a cell, and a body fluid. 
     
     
       4. The method of  claim 3 , wherein the first and/or the second biological sample is a body fluid selected from the group consisting of blood, sera, plasma, and cerebrospinal fluid. 
     
     
       5. The method of  claim 3 , wherein the first and/or the second biological sample is in the form of frozen plasma or serum. 
     
     
       6. The method of  claim 1 , wherein the second biological sample is obtained from the individual one day after administration of the first dose of the natalizumab. 
     
     
       7. The method of  claim 1 , wherein the soluble molecule is measured by a method selected from the group consisting of enzyme-linked immunosorbent assays (ELISA), radioimmunoassay (RIA), Western blotting, and microbead-based protein detection assay. 
     
     
       8. A method of treating multiple sclerosis in an individual, comprising:
 a) measuring a soluble molecule in a first biological sample obtained from the individual immediately before administration of natalizumab, wherein the soluble molecule is sVCAM and/or sMAdCAM; 
 b) administering the first dose of the natalizumab to the individual; 
 c) measuring the sVCAM and/or sMAdCAM in a second biological sample, wherein the second biological sample has been obtained from the individual within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after administration of the first dose of the natalizumab; 
 d) determining there is a decrease in the levels of the sVCAM and/or sMAdCAM between the first and second biological samples, wherein the decrease correlates with a decrease in alpha-4 integrin activity in the individual, and thereby determining whether there is a difference in alpha-4 integrin activity in the individual after administration of the first dose of natalizumab compared with before administration of the first dose of natalizumab; and 
 e) administering a second dose of natalizumab to the individual, wherein the second dose of natalizumab is calculated based on the decrease in the levels of the sVCAM and/or sMAdCAM between the first and second biological samples, wherein 
 
       the method comprises detecting a statistically significant decrease (p≤0.05) in the levels of sVCAM and/or sMAdCAM between the first and second biological samples, thereby determining that the first dose of natalizumab is effective and the method further comprises administering the second dose of natalizumab, wherein the second dose is the same as the first dose. 
     
     
       9. The method of  claim 8 , wherein alpha-4 integrin activity is alpha-4 beta-1 integrin activity, and wherein the soluble molecule is sVCAM. 
     
     
       10. The method of  claim 8 , wherein the first and/or the second biological sample is selected from the group consisting of a tissue, a cell, and a body fluid. 
     
     
       11. The method of  claim 10 , wherein the first and/or the second biological sample is a body fluid selected from the group consisting of blood, sera, plasma, and cerebrospinal fluid. 
     
     
       12. The method of  claim 10 , wherein the first and/or the second biological sample is in the form of frozen plasma or serum. 
     
     
       13. The method of  claim 8 , wherein the second biological sample is obtained from the individual one day after administration of the first dose of the natalizumab. 
     
     
       14. The method of  claim 8 , wherein the soluble molecule is measured by a method selected from the group consisting of enzyme-linked immunosorbent assays (ELISA), radioimmunoassay (RIA), Western blotting, and microbead-based protein detection assay.